Fresh leaves of the khat tree (Catha edulis Forsk.) are chewed for their euphoric properties in East Africa and parts of the Middle East, such as The Yemen. This review describes the history, cultivation and constituents of khat, and the social aspects of khat chewing in Yemen. The major pharmacologically active constituent of the fresh leaves is (--)-S-cathinone. The pharmacology of (--)-S-cathinone in the central nervous system and the peripheral effects are described. (--)-S-Cathinone is regarded as an amphetamine-like sympathomimetic amine and this mechanism of action is discussed in relation to the central stimulant actions and the cardiovascular effects of increasing blood pressure and heart rate. The risk factors associated with khat chewing are described, with emphasis on the reported increased incidence of acute myocardial infarction.
1. Owing to the considerable potential for manipulating the murine genome and, as a consequence, the increasing availability of genetically modified models of cardiovascular diseases, the mouse is fast becoming a cornerstone of animal research. However, progress in the use of various murine preparations is hampered by the lack of facilities and skills for the adequate physiological assessment of genetically modified mice. 2. We have attempted to address this problem by refining and characterizing a mouse isolated heart preparation that was originally developed for use with larger hearts. 3. We used the isolated buffer-perfused Langendorff preparation (perfused at constant flow or constant pressure) to characterize: (i) the frequency-response characteristics; (ii) heart isolation conditions; (iii) perfusion chamber conditions; (iv) temperature-function relationships; (v) stability over extended periods of perfusion; (vi) perfusate calcium-function relationships; (vii) pressure-volume relationships; (viii) pressure-rate relationships; and (ix) flow-function relationships.
Various putative drug targets for suppression of ischaemia‐induced ventricular fibrillation (VF) have been proposed, but therapeutic success in the suppression of sudden cardiac death (SCD) has been disappointing. Platelet‐activating factor (PAF) is a known component of the ischaemic milieu. We examined its arrhythmogenic activity, and its interaction with two other putative mediators, norepinephrine and K+, using an ischaemia‐free in vitro heart bioassay, and a specific PAF antagonist (BN‐50739).
PAF (0.1–100 nmol) was administered selectively to the left coronary bed of rat isolated hearts using a specially designed catheter. In some hearts, PAF was administered to the left coronary bed during concomitant regional perfusion with norepinephrine and/or K+. In separate studies, PAF accumulation in the perfused cardiac tissue was evaluated using 3H‐PAF.
PAF evoked ventricular arrhythmias concentration‐dependently (P<0.05). It also widened QT interval and reduced coronary flow selectively in the PAF‐exposed left coronary bed (both P<0.05). Two exposures of hearts to PAF were necessary to evoke the QT and rhythm effects.
The PAF‐induced arrhythmias and coronary vasoconstriction were partially suppressed by the PAF antagonist BN‐50739 (10 μM), although BN‐50739 itself widened QT interval.
K+ (8 and 15 mM) unexpectedly antagonised the arrhythmogenic effects of PAF without itself eliciting arrhythmias (P<0.05). Norepinephrine (0.1 μM) had little or no effect on the actions of PAF, while failing to evoke arrhythmias itself. Nevertheless, the combination of 15 mM K+ and 0.1 μM norepinephrine evoked arrhythmias of a severity similar to arrhythmias evoked by PAF alone, without adding to or diminishing the arrhythmogenic effects of PAF.
3H‐PAF accumulated in the cardiac tissue, with 43±5% still present 5 min after bolus administration, accounting for the need for two exposures of the heart to PAF for evocation of arrhythmias.
Thus, PAF, by activating specific receptors in the ventricle, can be expected to contribute to arrhythmogenesis during ischaemia. However, its interaction with other components of the ischaemic milieu is complex, and selective block of its actions (or its accumulation) in the ischaemic milieu is alone unlikely to reduce VF/SCD.
British Journal of Pharmacology (2004) 142, 352–366. doi:
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